DESCRIPTION Cationic Steroidal Antimicrobial-13 for Use as an Orthopedic Device Coating Abstract RELEVANCE: The Career Development Award-Level 1 will provide Dr. Sinclair with the mentoring and training necessary to establish him as an independent VA Career Scientist. This work, utilizing the novel polymer released antimicrobial delivery system to address the current limitations of antibiotic therapies, and the collaborations with his mentors will be the foundation on which Dr. Sinclair will establish his VA research career. The Center for Disease Control reports nearly 500,000 confirmed incidences of S. aureus and methicilin-resistant S. aureus (MRSA) occurring in the United States per year. This increasingly high number of MRSA cases can be attributed to the bacteria's evolved resistance toward antibiotic therapy. To address these issues, Cationic Steroidal Antimicrobial- 13 (CSA-13) will be incorporated into a silicone (Si) polymer coating and examined for its bactericidal potential when used as an orthopedic device coating. Preliminary in vitro testing has demonstrated greater than a 99% reduction of MRSA within 24 hours with exposure to titanium (Ti) plug implants coated with the 18% w/w Si polymer released CSA-13 antimicrobial. OBJECTIVES: 1) Provide Dr. Sinclair with the mentoring and training necessary to establish himself as a VA Career Scientist. 2) Combat resistant bacteria strain infections associated with common orthopedic device procedures through the use of the Si polymer released CSA- 13 antimicrobial. The long-term goals of this work are to foster Dr. Sinclair's continued progress toward the award of VA Career Scientist and to use the knowledge gained from his work with CSA-13 to reduce the incidence of device-related infection, minimize the time required for hospitalization, decrease the expense incurred by the VA health care system and patient, and reduce the number of stages required for revision procedures. HYPOTHESES: 1) The CSA-13 antimicrobial (18% w/w) will prevent infection caused by MRSA in vivo when eluted from the Si polymer coating on a porous coated titanium implant. 2) The rate and amount of periprosthetic bone ingrowth will not be adversely affected by the release of the CSA-13 antimicrobial. PROCEDURES: Four groups, each utilizing seven sheep, will receive a porous coated Ti bone plug in the medial aspect of the femoral condyle. Groups 1-3 will be inoculated with 200 l of 1x108 planktonic MRSA. The experimental group (Group 1) will have a porous coated Ti bone plug coated with a thin film of CSA-13 in a Si polymer (18% w/w), the polymer control (Group 2) will use only the Si coating (without CSA-13), to confirm an infection signal (Group 3) will use only the bone plug without CSA-13 or the Si coating, and Group 4 will serve as the surgical control; having neither CSA-13, Si coating, or bacteria added. The results of a power analysis indicated that an effect size of seven was required for statistical significance. SIGNIFICANCE OF FINDINGS: The success of this novel antimicrobial has the potential to significantly improve VA clinical care by reducing costs associated with primary and revision surgeries caused by perioperative device related infections. This research would also greatly improve the veteran's quality of life and reduce time required for hospitalization and rehabilitation by eliminating or significantly limiting the vetera's susceptibility to preoperative device related infections. PUBLIC HEALTH RELEVANCE: Cationic Steroidal Antimicrobial-13 for use as an Orthopedic Device Coating Project Narrative. The primary goal of this Career Development Award-Level 1 is to provide Dr. Sinclair with a unique pathway to independence. This will be accomplished with expert mentoring and advising from prolific scientists in the fields of orthopedic medicine and infectious disease. With their guidance and the support of the Career Development Award, Dr. Sinclair will work to develop a unique approach to address the limitations of current antibiotic therapy. The objective of the proposed research is to combat antibiotic resistant bacterial infections associated with common orthopedic devices through the use of a synthetic bacteria eliminating surface coating. The success of this program has the potential to reduce device-related infections, time required for hospitalization, the expense incurred by the VA Health Care System and its patients, as well as the number of stages required for revision procedures.